Dynamic and Self-Healable Chitosan/Hyaluronic Acid-Based In Situ-Forming Hydrogels.

In situ-forming, biodegradable, and self-healing hydrogels, which maintain their integrity after damage, owing to dynamic interactions, are essential biomaterials for bioapplications, such as tissue engineering and drug delivery. This work aims to develop in situ, biodegradable and self-healable hydrogels based on dynamic covalent bonds between N-succinyl chitosan (S-CHI) and oxidized aldehyde hyaluronic acid (A-HA). A robust effect of the molar ratio of both S-CHI and A-HA was observed on the swelling, mechanical stability, rheological properties and biodegradation kinetics of these hydrogels, being the stoichiometric ratio that which leads to the lowest swelling factor (×12), highest compression modulus (1.1·10−3 MPa), and slowest degradation (9 days). Besides, a rapid (3 s) self-repairing ability was demonstrated in the macro scale as well as by rheology and mechanical tests. Finally, the potential of these biomaterials was evidenced by cytotoxicity essay (>85%).

Electro and magnetoactive printed bi-functional actuators based on alginate hybrid hydrogels.

Soft materials are attracting much attention for the development of biostructures able to mimic the movement of natural systems by remote actuation. Multi-sensitive hydrogels are among the best materials for obtaining dynamic and biocompatible soft structures for soft actuators and related biomedical devices. Nevertheless, bioinks based on naturally occurring and stimuli responsive hydrogels able to be 3D printed continues being a challenge for advanced applications. In this work 3D printable electrically and magnetically responsive, non-cytotoxic, hybrid hydrogels based on alginate and zero monovalent iron nanoparticles (NPs) are presented. The effect of NPs addition on the physico-chemical properties of the hydrogels is addressed, together with its effect on the functional electroactive and magnetoactive response. NPs concentration up to 10 % do not affect the mechanical stability of the gels, while promoting an increase actuation response.

Photocrosslinkable and self-healable hydrogels of chitosan and hyaluronic acid.

Biocompatible and biodegradable hydrogels with biomimetic properties, such as self-repairing, are increasingly interesting for biomedical applications, particularly when they can be printed or in situ formed to mimic extracellular matrix or as personalized implantable devices in tissue regeneration or drug delivery. Photocrosslinkable hydrogels based on methacrylated chitosan (CHIMe) and hyaluronic acid that exhibit according with their composition, tuneable physico-chemical properties are here presented. The study of the conversion, gelation time, mechanical and rheological properties of photopolymerized CHIMe showed an optimal phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) initiator feed (0.1 % w). These photocrosslinkable hydrogels demonstrated being able to promote doubly crosslinked hydrogels with similar Young Moduli regardless the cycles of self-healing processes, and tailored swelling (25-70 swelling factor), mechanical (1 × 10-4-2 × 10-2 MPa) and rheological properties, as a function of polysaccharides relative content. Clear evidences have been found that fast photopolymerization of CHIMe/HA solutions leads to biocompatible (>80 % cell viability), biodegradable (20-24 days in hydrolytic medium) and robust self-healable hydrogels suitable for advanced biomedical and tissue engineering applications.

Risk Factors for Multidrug-Resistant Gram-Negative Bacteria Carriage upon Admission to the Intensive Care Unit.

Multidrug-resistant Gram-negative bacteria (MDR-GNB) are microorganisms that have acquired resistance to extended-spectrum antibacterials and constitute an emerging threat to public health. Although carriers are an important source of transmission in healthcare settings, data about risk factors for MDR-GNB carriage are limited. Therefore, we aimed to identify risk factors for MDR-GNB carriage upon intensive care unit (ICU) admission and to optimise screening strategies. We conducted a case-control study. Admissions of adult patients to the ICU of a 1000-bed hospital during a year were included. We collected sociodemographic, clinical and microbiological data and performed a multivariate logistic regression model. A total of 1342 patients resulted in 1476 episodes of ICU admission, 91 (6.2%) of whom harboured MDR-GNB (38.5% women; median age 63.9 years). The most frequently isolated pathogens were Escherichia coli (57%) and Klebsiella pneumoniae (16%). The most frequent resistance mechanism was production of extended-spectrum beta lactamases. MDR-GNB carriage was associated to liver cirrhosis (OR 6.54, 95% CI 2.17-19.17), previous MDR-GNB carriage (OR 5.34, 1.55-16.60), digestive surgery (OR 2.83, 1.29-5.89) and length of hospital stay (OR 1.01 per day, 1.00-1.03). Several risk factors for MDR-GNB carriage upon admission to a high-risk setting were identified; the main comorbidity was liver cirrhosis.

pH-Induced 3D Printable Chitosan Hydrogels for Soft Actuation.

Three-dimensional (3D) printing represents a suitable technology for the development of biomimetic scaffolds for biomedical and tissue engineering applications. However, hydrogel-based inks' printability remains a challenge due to their restricted print accuracy, mechanical properties, swelling or even cytotoxicity. Chitosan is a natural-derived polysaccharide that has arisen as a promising bioink due to its biodegradability, biocompatibility, sustainability and antibacterial properties, among others, as well as its ability to form hydrogels under the influence of a wide variety of mechanisms (thermal, ionic, pH, covalent, etc.). Its poor solubility at physiological pH, which has traditionally restricted its use, represents, on the contrary, the simplest way to induce chitosan gelation. Accordingly, herein a NaOH strong base was employed as gelling media for the direct 3D printing of chitosan structures. The obtained hydrogels were characterized in terms of morphology, chemical interactions, swelling and mechanical and rheological properties in order to evaluate the influence of the gelling solution's ionic strength on the hydrogel characteristics. Further, the influence of printing parameters, such as extrusion speed (300, 600 and 800 mm/min) and pressure (20-35 kPa) and the cytocompatibility were also analyzed. In addition, printed gels show an electro-induced motion due to their polycationic nature, which highlights their potential as soft actuators and active scaffolds.

3D printable self-healing hyaluronic acid/chitosan polycomplex hydrogels with drug release capability.

Multifunctional printable biomaterials are at the base of advanced biomedical applications. Chitosan (CHI) and hyaluronic acid (HA) allow the development of polycomplex hydrogels with tailorable properties, including self-healing and controlled drug release. This work correlates and optimizes the mucoadhesive, swelling, biodegradation, mechanical and rheological properties of HA/CHI polycomplex hydrogels with synthesis parameters such as polysaccharide content and complexation time, according to the interaction forces established between both polyelectrolytes. Related to these dynamic forces, the self-healing ability of the hydrogels was investigated together with the potential of the HA/CHI polycomplex hydrogels for 3D printing. Finally, their capability to modulate and promote controlled release of a variety of drugs (anionic and anti-inflammatory sodium diclofenac and the neutral antibiotic rifampicin) was demonstrated. Thus, the reported tunable properties, self-repair ability, printability and drug release properties, demonstrate the suitability of HA/CHI hydrogels for advanced biomedical applications.

Characterization of Phosphate Coatings: Influence of the Acid Pickling Conditions.

This research emphasizes the importance of the acid cleaning prior to the phosphate development on high-strength steel rods. It compares the phosphate properties achieved after different acid-pickling conditions. The most common inorganic acids were considered in this study. Additionally, taking into account the environmental and safety concerns of these acids, the assessment of a less harmful organic acid is presented. This study revealed significant differences in the coating morphology and chemical composition whereas no great changes were found in terms of the coating weight or porosity. Thus, hydrochloric and sulfuric acid promote the growth of a Fe-enriched phosphate layer with a less conductive character that is not developed after the pickling with phosphoric acid. The phosphate developed after the citric acid pickling is comparable to that developed after the inorganic acids although with a porosity slightly higher. The temperature of the citric acid bath is an important parameter that affects to the phosphate appearance, composition, and porosity.

Efficacy and safety of early treatment with sarilumab in hospitalised adults with COVID-19 presenting cytokine release syndrome (SARICOR STUDY): protocol of a phase II, open-label, randomised, multicentre, controlled clinical trial.

INTRODUCTION: About 25% of patients with COVID-19 develop acute respiratory distress syndrome (ARDS) associated with a high release of pro-inflammatory cytokines such as interleukin-6 (IL-6). The aim of the SARICOR study is to demonstrate that early administration of sarilumab (an IL-6 receptor inhibitor) in hospitalised patients with COVID-19, pulmonary infiltrates and a high IL-6 or D-dimer serum level could reduce the progression of ARDS requiring high-flow nasal oxygen or mechanical ventilation (non-invasive or invasive). METHODS AND ANALYSIS: Phase II, open-label, randomised, multicentre, controlled clinical trial to study the efficacy and safety of the administration of two doses of sarilumab (200 and 400 mg) plus best available therapy (BAT) in hospitalised adults with COVID-19 presenting cytokine release syndrome. This strategy will be compared with a BAT control group. The efficacy and safety will be monitored up to 28 days postadministration. A total of 120 patients will be recruited (40 patients in each arm). ETHICS AND DISSEMINATION: The clinical trial has been approved by the Research Ethics Committee of the coordinating centre and authorised by the Spanish Agency of Medicines and Medical Products. If the hypothesis is verified, the dissemination of the results could change clinical practice by increasing early administration of sarilumab in adult patients with COVID-19 presenting cytokine release syndrome, thus reducing intensive care unit admissions. TRIAL REGISTRATION NUMBER: NCT04357860.

Polysaccharide-Based In Situ Self-Healing Hydrogels for Tissue Engineering Applications.

In situ hydrogels have attracted increasing interest in recent years due to the need to develop effective and practical implantable platforms. Traditional hydrogels require surgical interventions to be implanted and are far from providing personalized medicine applications. However, in situ hydrogels offer a wide variety of advantages, such as a non-invasive nature due to their localized action or the ability to perfectly adapt to the place to be replaced regardless the size, shape or irregularities. In recent years, research has particularly focused on in situ hydrogels based on natural polysaccharides due to their promising properties such as biocompatibility, biodegradability and their ability to self-repair. This last property inspired in nature gives them the possibility of maintaining their integrity even after damage, owing to specific physical interactions or dynamic covalent bonds that provide reversible linkages. In this review, the different self-healing mechanisms, as well as the latest research on in situ self-healing hydrogels, is presented, together with the potential applications of these materials in tissue regeneration.

ß-Glycerol phosphate/genipin chitosan hydrogels: A comparative study of their properties and diclofenac delivery.

Thermosensitive hydrogels based on polysaccharides are suitable candidates for the design of biodegradable and biocompatible injectable drug delivery systems. Thus, the combination of chitosan (CHI) and ß-glycerol phosphate disodium salt (ß-GP) has been intensively investigated to develop thermo-induced physical gels. With the aim of exploring the possibilities of optimization of these hydrogels, in this work, chitosan, ß-GP and naturally extracted crosslinking agent, genipin (GEN), have been successfully combined, obtaining co-crosslinked hydrogels with both in situ physical and covalent crosslinking. A wide range of ß-GP concentrations have been selected in order to analyze its influence on a variety of properties, including gelation time, pore size, water uptake ability, in vitro hydrolytic and enzymatic degradation, mucoadhesion and mechanical and rheological properties. Furthermore, the potential application of the developed systems for the administration and controlled release of an anti-inflammatory anionic drug, such as diclofenac, has been successfully demonstrated.

Discordant retention of HIV-infected mothers and children: Evidence for a family-based approach from Southern Mozambique.

It is often assumed that children and their caregivers either stay in care together or discontinue together, but data is lacking on caregiver-child retention concordance. We sought to describe the pattern of care among a cohort of human immunodeficiency virus (HIV) infected children and mothers enrolled in care at the Manhiça District Hospital (MDH).This was a retrospective review of routine HIV clinical data collected under a larger prospective HIV cohort study at MDH. Children enrolling HIV care from January 2013 to November 2016 were identified and matched to their mother's HIV clinical data. Retention in care for mothers and children was assessed at 24 months after the child's enrolment. Multinomial logistic regression was performed to evaluate variables associated with retention discordance.For the 351 mother-child pairs included in the study, only 39% of mothers had concordant care status at baseline (23% already active in care, 16% initiated care concurrently with their children). At 24-months follow up, a total of 108 (31%) mother-child pairs were concordantly retained in care, 88 (26%) pairs were concordantly lost to follow up (LTFU), and 149 (43%) had discordant retention. Pairs with concurrent registration had a higher probability of being concordantly retained in care. Children who presented with advanced clinical or immunological stage had increased probability of being concordantly LTFU.High rates of LTFU as well as high proportions of discordant retention among mother-child pairs were found. Prioritization of a family-based care model that has the potential to improve retention for children and caregivers is recommended.

Synthesis and Characterization of Covalently Crosslinked pH-Responsive Hyaluronic Acid Nanogels: Effect of Synthesis Parameters.

Stable hyaluronic acid nanogels were obtained following the water-in-oil microemulsion method by covalent crosslinking with three biocompatible crosslinking agents: Divinyl sulfone, 1,4-butanediol diglycidyl ether (BDDE), and poly(ethylene glycol) bis(amine). All nanoparticles showed a pH-sensitive swelling behavior, according to the pKa value of hyaluronic acid, as a consequence of the ionization of the carboxylic moieties, as it was corroborated by zeta potential measurements. QELS studies were carried out to study the influence of the chemical structure of the crosslinking agents on the particle size of the obtained nanogels. In addition, the effect of the molecular weight of the biopolymer and the degree of crosslinking on the nanogels dimensions was also evaluated for BDDE crosslinked nanoparticles, which showed the highest pH-responsive response.

Serological immune response against ADAM10 pro-domain is associated with favourable prognosis in stage III colorectal cancer patients.

A humoral immune response against aberrant tumor proteins can be elicited in cancer patients, resulting in the production of auto-antibodies (Abs). By serological proteome analysis we identified the surface membrane protein ADAM10, a metalloproteinase that has a role in epithelial-tumor progression and invasion, as a target of the immune response in colorectal cancer (Crc). A screening carried out on the purified protein using testing cohorts of sera (Crc patients n = 57; control subjects n = 39) and validation cohorts of sera (Crc patients n = 49; control subjects n = 52) indicated that anti-ADAM10 auto-Abs were significantly induced in a large group (74%) of colon cancer patients, in particular in patients at stage II and III of the disease. Interestingly, in Crc patients classified as stage III disease, the presence of anti-ADAM10 auto-Abs in the sera was associated with a favourable follow-up with a significant shifting of the recurrence-free survival median time from 23 to 55 months. Even though the ADAM10 protein was expressed in Crc regardless the presence of auto-Abs, the immature/non-functional isoform of ADAM10 was highly expressed in the tumor of anti-ADAM10-positive patients and was the isoform targeted by the auto-Abs. In conclusion, the presence of anti-ADAM10 auto-Abs seems to reflect the increased tumor expression of the immunogenic immature-ADAM10 in a group of Crc patients, and is associated with a favourable prognosis in patients at stage III of the disease.

Natural Antibodies to Tumor-Associated Antigens.

Natural autoantibodies raised by humoral immune response to cancer can be exploited to identify potential tumor-associated antigens (TAAs), and might constitute new putative prognostic and/or diagnostic biomarkers. Here we describe how sera from tumor patients can be used to identify TAAs by screening antibody immunoreactivity against the cancer proteome resolved by two-dimensional gel electrophoresis.

Protein disulfide isomerase A3-specific Th1 effector cells infiltrate colon cancer tissue of patients with circulating anti-protein disulfide isomerase A3 autoantibodies.

To investigate novel colorectal cancer (CRC)-associated antigens that could be targets of humoral or cellular responses, we analyzed the reactivity of serum from a long-surviving CRC patient (for more than 100 months of follow-up) in clinical remission, by serologic proteome analysis. Two-dimensional Western blotting (2D-WB) and mass spectrometry analysis revealed a strong reactivity of this serum against protein disulfide isomerase A3 (PDIA3). Anti-PDIA3 antibodies are not a diagnostic marker of CRC, 2D-WB and Luminex analysis revealed that they were equally present in about 10% of sera from healthy subjects and CRC patients. Kaplan-Meier analysis of survival in CRC patient cohort, after 48 months of follow-up, showed a trend of higher survival in patients with increased levels of autoantibodies to PDIA3. Therefore, the interplay between the presence of these antibodies and T-cell response was investigated. Peripheral blood T cells from CRC patients with high immunoglobulin G (IgG) reactivity to PDIA3 also secreted interferon gamma (IFN-γ) when stimulated in vitro with recombinant PDIA3, whereas those from CRC with low IgG reactivity to PDIA3 did not. PDIA3-pulsed dendritic cells efficiently induced proliferation and IFN-γ production of autologous CD4(+) and CD8(+) T cells. Finally, ex vivo analysis of tumor-infiltrating T lymphocytes from CRC patients with autoantibodies to PDIA3 revealed that PDIA3-specific Th1 effector cells accumulated in tumor tissue. These data indicate that the presence of autoantibodies to PDIA3 favors the development of an efficient and specific T-cell response against PDIA3 in CRC patients. These results may be relevant for the design of novel immunotherapeutic strategies in CRC patients.